The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Chemotherapy-induced thrombocytopenia remains an unmet medical need because the current treating regimen employs transfusion of platelets that may be in short supply and carry a risk of viral contamination. On the other hand, recombinant human IL-11 can be given to a patient to stimulate platelet production. However IL-11 administration requires daily dosing, leading to marginal clinical efficacy and plasma expansion.
IL-11 is a cytokine and acts as a major signaling agent in hematopoiesis, and especially in the stimulation of megakaryocyte maturation. Action of IL-11 is typically mediated by the IL-11 receptor and glycoprotein gp130 with subsequent phosphorylation/activation of gp130. Clinical uses for IL-11 include treatment of side effects associated with chemotherapy, which is thought to enhance megakaryocytopoiesis and increase platelet counts. Recombinant human IL-11 is commercially available as NEUMEGA® (Oprelvekin, Wyeth-Ayerst) and is approved for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with non-myeloid malignancies who are at high risk of severe thrombocytopenia. NEUMEGA® is typically supplied in a single use vial containing 5 mg IL-11 as a lyophilized powder for reconstitution with 1 mL sterile water for injection (administered at a dose of 25-50 μg/kg/day). The most frequent adverse event associated with NEUMEGA™ is plasma expansion leading to life-threatening atrial arrhythmias, syncope, dyspnea, congestive heart failure, and pulmonary edema.
IL-11 is cleared from the circulatory system relatively quickly and as such requires multiple injections. For example, Neumega™ subcutaneously administrated in healthy men has a terminal half-life about 6.9 hours (Product Insert of Neumega™). The poor pharmacokinetics such as rapid renal excretion and proteolytic digestion, as well as its associated adverse effect often reduce clinical prevalence. Moreover, daily injection also means hospitalization to manage adverse event that not only adds on medical expense but also damages quality of life to patients. As a result, platelet transfusion remains the gold-standard for treating chemotherapy-induced thrombocytopenia (CIT).
Several attempts have been undertaken in the art to increase serum stability while maintaining beneficial therapeutic potential of such compositions. For example, US 2010/0098658 reports an IL-11 analog (mIL-11) in association with a polymer (PEG) that exhibited enhanced resistance to acidolysis and increased serum half-life. In another attempt to stabilize IL-11, as described in U.S. Pat. No. 8,133,480, cysteine variants of IL-11 were prepared and selected muteins were further modified with PEG to increase serum stability. While these modifications have improved serum stability or half-life of IL-11 to at least some degree, one or more disadvantages nevertheless remain, including marginal efficacy in myelosuppressive animals, complexity in production, repeated dosing, and formulation into injectable solution.
Because of lacking cysteine residues in IL-11, the '480 patent describes insertion of a cysteine residue in the C-terminal amino acid sequence, conferring a functional group to allow conjugation of a thiol-reactive polyethylene glycol chain. Although the biological activity was conserved, the introduction of cysteine may yield intermolecular dimers and the production yield of insect cells may be lower than bacterial production. Additionally the serum half-life of so modified IL-11 when administrated intravenously in male Sprague-Dawley rats was about 5.6 hr for 40 KD PEGylation, which is less than desirable. Moreover, in animal studies using cyclophosphamide-treated rats, the efficacy was marginal with the-other-day dosing scheme. Another employed PEG conjugation onto N-terminally truncated sequence of IL-11 with 20 KD PEG via amine or amide bonding was described in US 2010/0098658. Although the N-terminal truncation did not reduce its biological activity, the serum half-life administered subcutaneously in male Sprague-Dawley rats was about 8.5 hr, again falling short of desirable stability. Additionally, the efficacy in an animal disease model was unknown.
Linear or branched PEG of 20 KD conjugating onto amine groups of IL-11 was reported (Takagi et al. 2007, “Enhanced pharmacological activity of recombinant human interleukin-11 (rhIL11) by chemical modification with polyethylene glycol.” J Control Release, 119(3):271-278), such unspecific conjugation often resulted in multiple PEGylation via reaction with lysine, histidine, and tyrosine residues as well as N-terminal amines.
Other reports have demonstrated certain carbohydrate modifications on the “non-core” regions of IL-11 such as N-terminus and loops enhanced cell-stimulatory activities, suggesting these regions are perhaps designed to limit biological activity of IL-11 (Yanaka et al. 2011, “Non-core region modulates interleukin-11 signaling activity: generation of agonist and antagonist variants.” J. Biol. Chem., 286:8085-8093). However, no desirable modification was reported with stabilities and activities above unmodified IL-11.
Thus, even though several methods of stabilizing IL-11 are known in the art, all or almost all have one or more drawbacks, such as limited efficacy and requirement for repeated dosing. More importantly, even in modified form, adverse effects of IL-11 (e.g., plasma expansion) were not reduced. Therefore, there remains a need for improved compositions and methods to stabilize IL-11 while simultaneously alleviate adverse effects.